The microbiome represents a previously underappreciated influence on numerous biological processes. While most microbes express determinants that are distinct from self, many microbes synthesize surface antigens that resemble host-like structures as a form of molecular mimicry. Although adaptive immunity can recognize a nearly infinite range of antigenic determinants, tolerance reduces reactivity toward self-like antigens, creating a critical gap in adaptive immunity toward molecular mimicry. Thus, immunological protection against molecular mimicry likely resides within the innate arm of immunity. As molecular mimicry often reflects decoration of microbes with distinct mammalian-like carbohydrate antigens, we screened innate immune factors for carbohydrate binding activity. Our results demonstrate that several innate immune factors, in particular galectin-4 and galectin-8, bind and kill blood group B-positive microbes, providing a mechanism whereby blood group-positive individuals protect themselves against blood group molecular mimicry. As molecular mimicry is not limited to the blood group B antigen, and galectins can recognize a variety of mammalian-like structures, galectins may also provide innate immunity against a variety of microbes that utilize molecular mimicry. Furthermore, as blood group-positive microbes can stimulate naturally occurring anti-blood group antibodies and galectins target these microbes in vivo, galectin-mediated immunity may regulate the development of naturally occurring anti-blood group antibodies, which represent the most common immunological barrier to transfusion and transplantation. Thus, we hypothesize that galectins provide innate immunity against molecular mimicry, which in turn impacts the formation of naturally occurring anti-blood group antibodies. To test this, we will examine the following specific aims. 1) Examine the impact of galectins on anti-blood group antibody formation. 2) Determine whether galectins provide broad protection against molecular mimicry. 3) Define the specificity of galectin family members for microbial antigens. These studies develop new models, characterize new paradigms in immunology, and develop new tools to study host-pathogen interactions with broad implications in transfusion medicine, infectious disease and autoimmunity.